The present invention relates to a treatment for patients having congestive heart failure and/or elevated cholesterol blood levels by administering a therapeutically effective amount of 3,5-Diiodothyropropionic acid. The present invention further relates to a synthetic method to prepare 3,5-Diiodothyropropionic acid.
Congestive heart failure continues to be a major health problem, affecting about 4.6 million people in the United States, and its prevalence is predicted to increase over the next several decades. The magnitude of heart failure as a clinical problem has placed emphasis on the need to develop new treatment strategies.
One approach that has emerged is the use of thyroid hormone, which has unique physiologic and biochemical actions that make it a novel and potentially useful agent for treatment of heart failure. Thyroid hormone has been shown to act at the transcriptional level on the content of myocardial calcium cycling proteins to stimulate calcium uptake by sarcoplasmic reticulum. In addition, thyroid hormone causes a reciprocal shift in cardiac myosin heavy chain (MHC) isoform expression, increasing the expression of the high activity V1 isoform and decreasing the low activity V3 form. These biochemical alterations may underlie the ability of thyroid hormone to increase the rates of ventricular pressure development and relaxation.
Thyroid hormones include the L-forms of thyroxine (3,5,3xe2x80x25xe2x80x2-L-thyronine; hereinafter thyroxine or T4) and triiodothyronine (3xe2x80x2,3,5-L-triiodothyrone; hereinafter triiodothyronine or T3). 3xe2x80x2,5xe2x80x2,3-L-Triiodothyronine (hereinafter Reverse T3 or r T3), is a normal metabolite of T4. T4 is synthesized in the thyroid gland and is the circulating form of hormone found in plasma. Although small amounts of T3 are synthesized by the thyroid gland, the majority is formed from the metabolism of thyroxine in peripheral tissues by the enzyme 5xe2x80x2-monodeiodinase. The molecular basis for the actions of thyroid hormones is though to be mediated through the binding of T3 to chromatin-bound nuclear receptors. There are two major subtypes of the thyroid hormone receptor, TRxcex1 and TRxcex2, which are the products of two different genes. These genes are members of the c-erbA protooncogene family and are related to a large number of steroid and peptide hormone receptors collectively known as the steroid-thyroid hormone superfamily. The TR xcex1 andxcex2 subtypes are differentially expressed in various tissues.
Thyroxine, synthesized by methods such as described in U.S. Pat. No. 2,803,654, is the principle thyroid hormone in current clinical use. This is largely because of its long half-life of 6-7 days. Triiodothyronine, which is less strongly bound to plasma proteins and has a more rapid onset of action, is available for intravenous administration. However, T3 has a relatively short half-life of two days or less.
Numerous studies have been carried out to synthesize thyroid hormone analogs that mimic the actions of the natural hormones. The objective of most of these efforts has been to develop thyromimetics that lower plasma cholesterol without adverse cardiac effects. A series of thyroxine analogs and methods of synthesis are described in U.S. Pat. No. 3,109,023.
Thyroid hormone agonists that are highly selective for the thyroid hormone receptor xcex2 subtype are described in U.S. Pat. Nos. 5,883,294. 5,284,971 describes a class of thyromimetics, which have the distinguishing characteristic of a sulfonyl bridge in the diphenyl core.
A more recent development has been the use of thyroid hormones for the treatment of cardiovascular compromise. A method for the treatment of patients with sudden (acute) cardiovascular compromise by administration of thyroid hormone is described in U.S. Pat. No. 5,158,978. The method teaches administration of T4 and T3 after cardiac arrest by injection into a vein, a central venous catheter, into the pulmonary circulation or directly into the heart.
Short-term intravenous administration of T3 to patients with advanced congestive failure has been shown to improve cardiac output and decrease arterial vascular resistance. Oral administration of L-thyroxine also has been shown to improve cardiac performance and exercise capacity in patients with idiopathic dilated cardiomyopathy when given for two weeks and 3 months. Although the number of patients in these studies was small, the results were generally favorable and established the basis for further investigation into the safety and potential benefits of treatment of heart failure with thyroid hormone or thyroid hormone analogs.
Because of potential adverse effects of thyroid hormone, such as metabolic stimulation and tachycardia, what is required are thyroid hormone analogs with fewer undesirable side effects. Applicants have found that 3,5-Diiodothyropropionic acid (DITPA) is a thyroid hormone analog that increases cardiac performance with approximately half of the chronotropic effect and less metabolic stimulation than L-thyroxine. Like thyroid hormone, DITPA binds to nuclear T3 receptors of the c-erbA proto-oncogene family. DITPA has been shown to improve left ventricular (LV) performance in post-infarction experimental models of heart failure when administered alone or in combination with an angiotensin I-converting enzyme inhibitor.
In addition to its well-known chronotropic and inotropic actions on the heart, thyroid hormone decreases arterial resistance, venous resistance and venous compliance. The net effect of these changes is to increase cardiac output more than arterial pressure, resulting in decreased calculated arterial vascular resistance. When used in experimental models of heart failure DITPA acts similarly to thyroid hormone, affecting both the heart and the peripheral circulation. Loss of the normal increase in contractility with heart rate, referred to as the positive force-frequency relationship, has been reported both in failing human myocardium and in animal models of heart failure. DITPA administration prevents the flattened contraction-frequency relationship in single myocytes from infarcted rabbit hearts. DITPA improves myocyte function, enhances calcium transport in the sarcoplasmic reticulum (SR) and prevents the down regulation of SR proteins associated with post-infarction heart failure in rabbits. In normal primates, DITPA enhances the in vivo force-frequency and relaxation-frequency relationships in a manner similar to thyroid hormone. DITPA is able to bring about these hemodynamic changes without increasing cardiac mass appreciably or adversely affecting ventricular dimensions. A morphometric analysis indicates that in post-infarction rats treated with DITPA there is an increase in capillary growth in the border zone around the infarct.
Applicants have found that 3,5-Diiodothyropropionic acid (DITPA) is a thyroid hormone analog that increases cardiac performance with approximately half of the chronotropic effect and less metabolic stimulation than L-thyroxine. Like thyroid hormone, DITPA binds to nuclear T3 receptors of the c-erbA proto-oncogene family. DITPA has been shown to improve left ventricular (LV) performance in post-infarction experimental models of heart failure when administered alone or in combination with an angiotensin I-converting enzyme inhibitor.
In addition to its well-known chronotropic and inotropic actions on the heart, thyroid hormone decreases arterial resistance, venous resistance and venous compliance. The net effect of these changes is to increase cardiac output more than arterial pressure, resulting in decreased calculated arterial vascular resistance.
When used in experimental models of heart failure DITPA acts similarly to thyroid hormone, affecting both the heart and the peripheral circulation. Loss of the normal increase in contractility with heart rate, referred to as the positive force-frequency relationship, has been reported both in failing human myocardium and in animal models of heart failure. DITPA administration prevents the flattened contraction-frequency relationship in single myocytes from infarcted rabbit hearts. In normal primates, DITPA enhances the in vivo force-frequency and relaxation-frequency relationships in a manner similar to thyroid hormone. DITPA is able to bring about these hemodynamic changes without increasing cardiac mass appreciably or adversely affecting ventricular dimensions. A morphometric analysis indicates that in post-infarction rats treated with DITPA there is an increase in capillary growth in the border zone around the infarct.
A dose-ranging study of DITPA was performed in seven normal volunteers. After establishing that the drug was well tolerated, a double-blind comparison of the effects of DITPA versus placebo was carried out in 19 patients with congestive failure.
In overview, DITPA was synthesized following good manufacturing procedures by coupling dianisoleiodium trifluoroacetate with ethyl-3-(3,5-diiodo-4-hydroxyphenyl)-propionate followed by removal of the methyl and ethyl protective groups. This coupling strategy does not produce T3 or T4 as by products because the compound giving rise to the outer ring does not contain iodine and the side chain of the inner ring reactant lacks an amino group.
The structure of the DITPA prepared using this synthetic route was authenticated by proton magnetic resonance and its purity was checked by reverse phase HPLC. The principle impurity was identified as the ethyl ester of DITPA. Only batches of the final compound with greater than 95% purity were used in this study.
Applicants"" synthesis of DITPA uses 3-(4-hydroxyphenyl)-propionic acid, compound I shown below, as a starting material. In a first synthetic step, compound I is reacted with potassium iodide/iodine, and then with methylamine, to form 3-(3,5-diiodo-4-hydroxyphenyl) propionic acid, compound II. 
Compound II is next reacted with ethanol, using p-toluenesulfonic acid as a catalyst, to form ethyl-3-(3,5-diiodo-4-hydroxyphenyl)propionate, compound III. 
Compound III is subsequently reacted with coupling agent dianisoleiodonium trifluoroacetate.
Coupling agent dianisoleiodonium trifluoroacetate is prepared by first reacting trifluoroacetic acid, compound IV, with red fuming nitric acid and iodine to form iodine(III)trifluoroacetate, compound V. 
In a subsequent step, compound V is reacted with anisole, i.e. methoxybenzene, to form dianisoleiodonium trifluoroacetate, compound VI. Applicants use trifluoroacetate as the counterion in compound VI because use of other counterions results in compounds that are more hygroscopic, and therefore, likely have limited shelf lives. 
Ethyl-3-(3,5-diiodo-4-hydroxyphenyl)propionate, compound III, is next reacted with dianisoleiodonium trifluoroacetate, compound VI, to form ethyl-3-(4xe2x80x2-methoxy-3,5-diiodothyro) propionate, compound VII. 
In the final step of Applicants"" synthetic method, ethyl-3-(4xe2x80x2-methoxy-3,5-diiodothyro) propionate, compound VII, is reacted with hydrogen iodide and glacial acid to hydrolyze both the ethyl ester and the methyl ether to give DITPA. 
The following examples are presented to further illustrate to persons skilled in the art how to synthesize DITPA. These examples are not intended as limitations, however, upon the scope of Applicants"" invention, which is defined only by the appended claims.